This application describes a five-year research career development program in the study of evolutionarily conserved mechanisms of innate immunity. The research program will be conducted under the mentorship of Professor Frederick Ausubel in the Department of Molecular Biology, Massachusetts General Hospital, and the Department of Genetics, Harvard Medical School. The candidate is trained in Infectious Diseases and previously completed graduate training in biochemistry. The proposed research career development program will provide training in genetic analysis, a new field of research for the candidate, in preparation for a career as an independent physician-scientist studying evolutionarily conserved mechanisms of innate immunity in the genetically tractable organism, Caenorhabditis elegans. The mammalian innate immune system represents the first line of defense against pathogens, playing central roles in the recognition of pathogens and the recruitment of the adaptive immune system. Derangement of pathways of innate immunity is implicated in the pathogenesis of septic shock. Evidence from studies of insect immunity has established that critical elements of the human innate immune system are evolutionarily conserved. Recently, the candidate in collaboration with other members in the Ausubel laboratory has shown that a highly conserved p38 MAP kinase signaling pathway is required for the nematode defense against bacterial pathogens. The candidate intends to carry out a genetic and functional genomic dissection of the p38 and JNK MAP kinase signaling pathways involved in the C. elegans immune response using a combination of microarray gene expression analysis, functional genomic analysis with RNAi, and a forward genetic suppressor screen. The basic underlying hypothesis of this proposal is that the study of C. elegans immunity will reveal evolutionarily conserved mechanisms of innate defense against pathogen attack.